EP0116495B1 - 17-Dithiocétals d'androstènes - Google Patents

17-Dithiocétals d'androstènes Download PDF

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Publication number
EP0116495B1
EP0116495B1 EP84400160A EP84400160A EP0116495B1 EP 0116495 B1 EP0116495 B1 EP 0116495B1 EP 84400160 A EP84400160 A EP 84400160A EP 84400160 A EP84400160 A EP 84400160A EP 0116495 B1 EP0116495 B1 EP 0116495B1
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Prior art keywords
steroid
hydrogen
formula
accordance
alkyl
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EP0116495A1 (fr
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Ravi K. Varma
Donald S. Karanewsky
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ER Squibb and Sons LLC
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ER Squibb and Sons LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0038—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 with an androstane skeleton, including 18- or 19-substituted derivatives, 18-nor derivatives and also derivatives where position 17-beta is substituted by a carbon atom not directly bonded to a further carbon atom and not being part of an amide group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0003—Androstane derivatives
    • C07J1/0011—Androstane derivatives substituted in position 17 by a keto group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
    • C07J31/003—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring the S atom directly linked to a ring carbon atom of the cyclopenta(a)hydrophenanthrene skeleton

Definitions

  • R 1 and R 2 is alkyl, aryl, arylalkyl, or cycloalkyl, and the other is mono- or difluoroalkyl;
  • aryl refers to phenyl substituted with one or two alkyl, alkoxy or halogen groups.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • alkyl and “alkoxy”, as used throughout the specification either individually or as part of a larger group, refer to groups having 1 to 12 carbon atoms.
  • cycloalkyl as used throughout the specification either individually or as part of a larger group, refer to groups having 3, 4, 5, 6 or 7 carbon atoms.
  • alkanoyl refers to groups having 2 to 13 carbon atoms.
  • US ⁇ A ⁇ 2,840,577 discloses 17-thio derivatives of estratrien-3-ol and of estratetraen-3-ol which are useful as estrogenic and anabolic agents and in the treatment of degenerative diseases associated with abnormal cholesterol metabolism.
  • US-A-4,091,036 discloses androstenes intermediates wherein the D-ring has the formula wherein R f is alkyl or aryl, and both R, groups are the same.
  • US-A-4,361,559 discloses androstene-17-dithioketals wherein the D-ring has the formula wherein Rg and R h are the same or different and each is alkyl, cycloalkyl, or aryl.
  • US ⁇ A ⁇ 4,420,428 discloses androstene-17-dithioketals wherein the D-ring has the formula wherein R 1 and R 2 are the same or different and each may be alkyl, cycloalkyl, aryl or arylalkyl, which are 5 useful as antiinflammatory agents.
  • the present invention relates to androstene-17-dithioketals wherein the substituents on the respective sulfur atoms are different, one of the substituents being mono- or difluoroalkyl.
  • the steroids of formula I, and the 1,2-dehydro, and 6,7-dehydro derivatives thereof, are topical antiinflammatory agents that can be used to treat skin conditions such as dermatitis, psoriasis, sunburn, eczema, neurodermatitis, or anogenital pruritus, and in inhalation therapy for topical treatment of allergy and asthma.
  • the topical antiinflammatory steroids of this invention may be administerd in a conventional pharmaceutical carrier in the form of a cream, ointment, lotion or the like.
  • the steroids will preferably be used in the range of 0.01 to 5.0% by weight of the vehicle, preferably 0.05 to 2.0% by weight of the vehicle.
  • topical antiinflammatory steroids of this invention may be administered in the conventional manner, e.g., as solid medicament which has been atomized.
  • United States patents 3,948,264 and 4,147,166 are exemplary of the literature which describes devices that can be used to administer solid medicaments for inhalation therapy.
  • the steroids of formula I, and the 1,2-dehydro and 6,7-dehydro derivatives thereof, wherein R 1 is alkyl, aryl, arylalkyl or cycloalkyl, can be prepared utilizing androstenes having the formula In formula II, and throughout the specification, a broken line in the steroid rings indicates the optional presence of ethylenic unsaturation, and the symbol R 7 represents alkyl, aryl, arylalkyl and cycloalkyl.
  • Z is a "leaving group" such as a halogen (preferably iodine or bromine) or an alkyl or arylsulfonyl compound (preferably methanesulfonyl ortoluenesulfonyl) and R 8 is mono- or difluoroalkyl.
  • the reaction is preferably carried out in the presence of a weak organic or inorganic base.
  • the steroid or formula I wherein R 1 is alkyl, aryl, arylalkyl or cycloalkyl can be prepared utilizing androstenes having the formula Reaction of a steroid of formula V with a thiol having the formula yields the corresponding steroid having the formula as a mixture of isomers.
  • the reaction is run in the presence of a Lewis acid (e.g., boron trifluoride etherate) and will preferably be run at a reduced temperature (i.e., about -20°C to -100°C).
  • a reduced temperature i.e., about -20°C to -100°C
  • the steroids of formula I, and the 1,2-dehydro, and 6,7-dehydro derivatives thereof, wherein R 2 is alkyl, aryl, arylalkyl or cycloalkyl, can be rpepared by alkkylation of the corresponding 17-thione having the formula Reaction of a steroid of formula IX with a compound of formula III (i.e., a compound having the formula R 8 ⁇ Z) yields the corresponding steroid having the formula
  • a steroid of formula X can be reacted with a thiol having the formula in the presence of a Lewis acid to yield the corresponding product having the formula
  • Steroids of formulas II and V can be prepared from the corresponding steroid having the formula
  • the androstenes of formula XIV wherein R 3 is hydroxy can be prepared by oxidation of the corresponding androstene having the formula with potassium permanganate in the presence of formic acid.
  • the oxidation reaction yields the corresponding 16a(and 16)3)-hydroxyandrostene-3,17-dione.
  • These can be acylated using art-recognized procedures to yield the corresponding 16-alkanoyloxy derivative.
  • Reaction of an androstene of formula XIV with a thiol having the formula in the presence of a Lewis acid yields a steroid having the formula
  • the reaction can be run in an organic solvent (e.g., a halogenated hydrocarbon), or a mixture of organic solvents.
  • Reaction conditions are not critical and the reaction can be conveniently run at room temperature, preferably in an inert atmosphere, (e.g., argon or nitrogen). Better yields can be obtained with relatively short reaction times (less than 1 hour).
  • dimethylformamide dialkyl acetal preferably dimethylformamide dimethyl acetal
  • Exposure of the crude reaction products, which frequently contain products derived from reaction of the A and B rings with thiols ("over-reacted products") to certain dethiolating agents well known in the art (e.g., methyl iodide in aqueous acetone) also improves the yields.
  • the steroids of formula XVII can be heated, either neat or in an inert solvent (e.g., diethylbenzene or dichlorobenzene) to yield the desired steroids of formula V.
  • steroids of formula XVII can be oxidized with a peracid (e.g., m-chloroperbenzoic acid) at low temperature (from about -78°C to 0°C) and the resulting monosulfoxide heated in an inert low boiling solvent to give the desired steroids of formula V.
  • a peracid e.g., m-chloroperbenzoic acid
  • compounds of formula V, wherein R 3 is chlorine, bromine, alkylthio, or arylthio can be prepared from the corresponding steroid of formula V wherein R 3 is hydrogen; e.g., a steroid having the formula Utilizing the procedure described in United States patent 4,265,815, issued May 15, 1981, a steroid of formula V wherein R 3 is chlorine or bromine can be obtained by reacting a steroid of formula XVIII with the appropriate N-halosuccinimide, or with chlorine or bromine, preferably in a halogenated hydrocarbon solvent.
  • Steroids of formula V wherein R 3 is alkylthio or arylthio can be obtained by reacting the corresponding steroid of formula XVIII with an alkyl or aryl sulfenyl halide, preferably in a halogenated hydrocarbon solvent.
  • Steroids of formula 11 can be obtained by recacting a steroid of formula V with hydrogen sulfide.
  • the reaction is run in the presence of a Lewis acid (e.g., boron trifluoride etherate) and will preferably be run at a reduced temperature (i.e., about 0°C to -20°C).
  • a Lewis acid e.g., boron trifluoride etherate
  • the 17-thione androstenes of formula IX are novel compounds, and as such, they form an integral part of this invention, as does the following method for their preparation.
  • Treatment of a hemithioketal of formula II with a tertiary amine base (e.g., triethylamine) or with an alkali metal (preferably potassium or sodium) carbonate yields the corresponding 17-thione androstene of formula IX.
  • the reaction is preferably run in an organic solvent such as dimethylformamide, tetrahydrofuran, or benzene.
  • An exemplary family of protecting groups is the acyl family, e.g., alkanoyl groups such as acetyl.
  • Means for protection and deprotection of the 11-hydroxyl group are well-known in the art.
  • reaction was then quenched by treatment with methanolic sodium hydroxide (1.5 ml of a solution prepared by dissolving 1.0 g sodium hydroxide in 15.0 ml methanol) at -78°C and immediately partitioned between dichloromethane and 5% potassium bisulfate. The organic phase was washed with water, dried over sodium sulfate and evaporated. Recrystallization of the residue from ethyl acetate/hexane gave the title com D ound (340 ma) as white needles. meltina point 152°-153°C.
  • the reaction was then quenched by treatment with methanolic sodium hydroxide (1.5 ml of a solution prepared by dissolving 1.0 g of sodium hydroxide in 15.0 ml of methanol) at -78°C and immediately partitioned between dichloromethane and 5% potassium bisulfate. The organic phase was washed with water, dried over sodium sulfate and evaporated. The residue was taken up in tetrahydrofuran (10.0 ml) and methanol (5.0 ml) and treated with a 3N sodium hydroxide solution (0.5 ml, 1.5 mmole) and stirred at room temperature under argon for 1 hour.
  • methanolic sodium hydroxide 1.5 ml of a solution prepared by dissolving 1.0 g of sodium hydroxide in 15.0 ml of methanol

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Rheumatology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Steroid Compounds (AREA)
  • Dental Preparations (AREA)
  • Lubricants (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Claims (15)

1. Stéroïde de formule
Figure imgb0033
éventuellement sous la forme d'un dérivé 1,2-déhydro ou 6,7-déhydro, formule dans laquelle
l'une de R1 et R2 est un radical alkyle, aryle, arylalkyle ou cycloalkyle, et l'autre est un radical mono- ou di-fluoroalkyle;
R3 est un atome d'hydrogène, un groupement hydroxy, un radical alcoxy ou aryloxy, un groupement oxo ou méthylène, un radical alkylthio, arylthio, alcanoyle ou alcanoyloxy, ou un atome de fluor;
R4 est un groupement carbonyle, β-hydroxyméthylène ou β-acétyloxyméthylène;
R5 est un atome d'hydrogène ou d'halogène; et
R6 est un atome d'hydrogène, un radical méthyle, un groupement hydroxy, un radical alcanoyle ou alcanoyloxy ou un atome d'halogène,
le radical aryle étant un radical phényle éventuellement substitué par un ou deux radicaux alkyle ou alcoxy ou atomes d'halogène, les radicaux alkyle et alcoxy ayant de 1 à 12 atomes de carbone, le radical cycloalkyle ayant 3, 4, 5, 6 ou 7 atomes de carbone, le radical alcanoyle ayant de 1 à 13 atomes de carbone, et les radicaux alcényle et alcynyle ayant de 2 à 13 atomes de carbone.
2. Stéroïde selon la revendication 1, dans la formule duquel R1 est un radical alkyle, aryle, arylalkyle ou cycloalkyle.
3. Stéroïde selon la revendication 1, dans la formule duquel R2 est un radical alkyle, aryle, arylalkyle ou cycloalkyle.
4. Stéroïde selon la revendication 1, dans la formule duquel R1 est le radical méthyle ou éthyle.
5. Stéroïde selon la revendication 1, dans la formule duquel R2 est le radical méthyle ou éthyle.
6. Stéroïde selon la revendication 1, dans la formule duquel R1 est un radical mono- ou di-fluoroalkyle.
7. Stéroïde selon la revendication 1, dans la formule duquel R2 est un radical mono- ou di-fluoroalkyle.
8. Stéroïde selon la revendication 1, dans la formule duquel R4 est le groupement β-hydroxyméthylène.
9. Stéroïde selon la revendication 1, dans la formule duquel R5 est un atome de fluor.
10. Stéroïde selon la revendication 1, dans la formule duquel R6 est un atome d'hydrogène.
11. Stéroïde selon la revendication 1, dans la formule duquel R4 est le groupement β-hydroxy- méthylène, R5 est un atome de fluor et R6 est un atome d'hydrogène.
12. Stéroïde selon la revendication 1, qui est la (11β,17α)-17-(éthylthio)-9-fluoro-17-[(2-fluoréthyl)thio]-11-hydroxyandrosta-1,4-dién-3-one.
13. Stéroïde selon la revendication 1, qui est la (11β,17β)-9-fluoro-17-[(2-fluoréthyl)thio]-11-hydroxy-17-propylthioandrosta-1,4-dién-3-one.
14. En tant qu'intermédiaire pour la préparation d'un stéroïde selon la revendication 1, stéroïde de formule
Figure imgb0034
éventuellement sous la forme d'un dérivé 1,2-déhydro ou 6,7-déhydro, formule dans laquelle
R3 est un atome d'hydrogène, un groupement hydroxy, un radical alcoxy ou aryloxy, un groupement oxo ou méthylène, un radical alkylthio, arylthio, alcanoyle ou alcanoyloxy, ou un atome de fluor;
R4 est un groupement carbonyle, β-hydroxyméthylène ou β-acétyloxyméthylène;
R5 est un atome d'hydrogène ou d'halogène; et
Re est un atome d'hydrogène, un radical méthyle, un groupement hydroxy, un radical alcanoyle ou alcanoyloxy ou un atome d'halogène, les radicaux aryle, alkyle, alcoxy et alcanoyle étant tels que définis dans la revendication 1.
15. Procédé de préparation d'un stéroïde selon la revendication 14, qui consiste à traiter un stéroïde correspondant, de formule
Figure imgb0035
dans laquelle
R3 est un atome d'hydrogène, un groupement hydroxy, un radical alcoxy ou aryloxy, un groupement oxo ou méthylène, un radical alkylthio, arylthio, alcanoyle ou alcanoyloxy, ou un atome de fluor;
R4 est un groupement carbonyle, β-hydroxyméthylène ou β-acétyloxyméthylène;
Rs est un atome d'hydrogène ou d'halogène;
R6 est un atome d'hydrogène, un radical méthyle, un groupement hydroxy, un radical alcanoyle ou alcanoyloxy ou un atome d'halogène; et
R7 est un radical alkyle, aryle, arylalkyle ou cycloalkyle,
les radicaux alcoxy, aryle, alkyle, alcanoyle et cycloalkyle étant tels que définis dans la revendication 1, éventuellement sous la forme d'un dérivé 1,2-déhydro ou 6,7-déhydro, par une amine tertiaire base ou par un carbonate de métal alcalin, dans une base organique.
EP84400160A 1983-01-31 1984-01-25 17-Dithiocétals d'androstènes Expired EP0116495B1 (fr)

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US462164 1983-01-31
US06/462,164 US4427592A (en) 1983-01-31 1983-01-31 Androstene-17-dithioketals

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EP0116495B1 true EP0116495B1 (fr) 1987-11-19

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EP (1) EP0116495B1 (fr)
JP (1) JPS59144800A (fr)
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Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4427592A (en) * 1983-01-31 1984-01-24 E. R. Squibb & Sons, Inc. Androstene-17-dithioketals
US4529548A (en) * 1984-05-07 1985-07-16 E. R. Squibb & Sons, Inc. 17β-(substituted thio)androstenes
US4528138A (en) * 1984-06-20 1985-07-09 E. R. Squibb & Sons, Inc. 16-Keto-17-substituted thia-17-alkyl(or alkenyl or alkynyl) androstenes
US4529547A (en) * 1984-06-20 1985-07-16 E.R. Squibb & Sons, Inc. 17-(substituted thio)-17-(substituted dithio)androstenes
US4891367A (en) * 1987-04-22 1990-01-02 Merrell Dow Pharmaceuticals Inc. 17β-(cyclopropyloxy)androst-5-en-3β-ol and related compounds useful as C17-20 lyase inhibitors

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2840577A (en) * 1956-12-21 1958-06-24 Searle & Co 17-thio derivatives of estratrien-3-ol and of estratetraen-3-ol
US4091036A (en) * 1977-05-12 1978-05-23 E. R. Squibb & Sons, Inc. 17-Alkylthio (and arylthio)-1',2',3',4'-tetrahydroandrosteno [16 α, 17 α-b]naphthalenes and derivatives
US4361559A (en) * 1981-08-20 1982-11-30 E. R. Squibb & Sons, Inc. Antiinflammatory 17,17-bis (substituted thio) androstenes
US4420428A (en) * 1982-12-27 1983-12-13 E. R. Squibb & Sons, Inc. 16-Ketoandrostene-17-dithioketals
US4427592A (en) * 1983-01-31 1984-01-24 E. R. Squibb & Sons, Inc. Androstene-17-dithioketals

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ZA84580B (en) 1984-09-26
DK41684A (da) 1984-08-01
IE56613B1 (en) 1991-10-09
US4427592A (en) 1984-01-24
AU562027B2 (en) 1987-05-28
HU193734B (en) 1987-11-30
JPS59144800A (ja) 1984-08-18
DE3467580T (fr) 1987-12-23
IE840189L (en) 1984-07-31
ATE30918T1 (de) 1987-12-15
AU2382684A (en) 1984-08-02
CA1205463A (fr) 1986-06-03
DE3467580D1 (de) 1987-12-23
DK41684D0 (da) 1984-01-30
HU187551B (en) 1986-01-28
EP0116495A1 (fr) 1984-08-22

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